The Best Folate to Take During Pregnancy with MTHFR

Folate is one of the most important nutrients for human health, and demands a substantial increase during pregnancy. Folate is required for DNA production and replication, correct cell division, activating B12, converting homocysteine to methionine, and supporting the synthesis of SAMe (S-adenosylmethionine) required for methylation.

During pregnancy, adequate supplementation with folate is crucial for proper methylation, which in turn contributes to the healthy growth and development of an unborn child. Impaired methylation has been linked to many pregnancy complications, including miscarriage, neural tube defects, preeclampsia, and poor neonatal brain development.

For this reason, women who are considering starting a family are generally recommended to take folic acid. Supplementation is advised both pre-conception and throughout the pregnancy, especially during the first 12 weeks. 

HOWEVER, “folic acid” and “folate” are not the same. Folate is the natural form of the nutrient, while folic acid is the synthetic form, often used in supplements and fortified foods.

However, women with an MTHFR mutation are unable to convert folic acid into its usable form (L-Methylfolate), which can lead to folate deficiency or, worse still, folic acid buildup. 

This article will discuss the different types of folate supplements and their advantages/disadvantages. We will explain the best form of folate to take during pregnancy and the right dosage, and how to source a quality supplement.

There are several different forms of oral folate supplements available to clinicians and the general public. Numerous studies have assessed the efficacy of folate supplements for different conditions and disease states, but little is shared about the absorption and bioavailability of different folate supplements.

Knowing the bioavailability of various forms of folate supplements is crucial for maintaining adequate levels in the body. 

Types of folate supplements include:

Folic acid is scientifically known as pteroylmonoglutamic acid. It is the synthetic form of vitamin B9, commonly used in dietary supplements, fortified foods, and beverages. It is a mono-glutamate form, and it is not found in nature.

Folic acid must be converted to L-5-Methyltetrahydrofolate (L-methylfolate)—the predominant form of folate in the body—to be used in biological processes.

Folinic acid is the form contained in leucovorin, which is used when a patient with cancer is treated with methotrexate. It is a vitamer: a molecule that substitutes for a recognized vitamin. It skips some of the steps required for the production of methylfolate in the body and is, therefore, more active than folic acid. 

However, it is still unable to be properly converted into the fully active L-Methylfolate by someone with the MTHFR mutation.

Dihydrofolic acid (DHF) is a derivative of folic acid, which is converted to tetrahydrofolic acid by the enzyme dihydrofolate reductase.

Tetrahydrofolic acid is then converted into 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase.

Levomefolic acid is also known as L-5-MTHF, L-methylfolate, L-5-methyltetrahydrofolate, (6S)-5-methyltetrahydrofolate, and (6S)-5-MTHF). It is the primary form of biologically active folate used in the body for DNA reproduction, the cysteine cycle, and the regulation of homocysteine. 

The active isomer can be written in two different ways, but both mean the same thing chemically.  “L” or “6S” refer to the absorbable or usable form of folate (i.e. L-5-Methylfolate or (6S)-5-Methylfolate).

Merck holds a patent on a specific type of calcium salt of the “L” isomer (which is marketed as Metafolin® and licenses other companies to make that compound and distribute it in the United States. It is a natural form of biologically active folate used in supplements and prenatal multivitamins. 

Calcium L-methylfolate (L-5-MTHF-Ca) is a source of folate and an alternative to folic acid for use in food and supplements. 

Magnafolate® PRO is a methylfolate called L-5-MTHF, which is shown to be the most active form of folate in plasma circulation. When compared with ordinary folate, Magnafolate® PRO was found to be absorbed faster and utilized more quickly in the body. It has also been clinically tested as the world’s purest methylfolate.

A recent study found that L-5-MTHF-Ca significantly boosted immune function over just five weeks of supplementation. 

Extrafolate-S® is similar to Metafolin® in that it is a calcium-salt-based molecule that the (6S) isomer of 5-MTHF is bound to. The significant difference between the ingredients Extrafolate-S® and Metafolin® is the salt molecule’s form type which translates into stability. Extrafolate-S® methylfolate is an amorphous salt form, and the Metafolin® methylfolate is a crystalline salt form (Type I). 

A crystalline salt molecule is more stable, which means that Merck’s compound is not as likely to lose potency over time.

Quatrefolic® is a glucosamine salt of (6S)-5-methyltetrahydrofolate and is described as the ‘fourth generation folate.’ Studies in rats have demonstrated an enhanced oral bioavailability in comparison to folic acid and other bioactive folates.

The MTHFR mutation reduces the body’s ability to metabolize folate. A homozygous C667T mutation is especially serious, with enzyme function at only about 30%. Research suggests that women with an MTHFR polymorphism have up to a 75% reduction in the capacity to form active folate  (5-MTHF: 5-methyltetrahydrofolate).

A heterozygous C677T is around 65% enzyme activity.

Essentially, these polymorphisms result in less biologically available L-methylfolate in the body. For this reason, those with an MTHFR mutation are strongly urged to supplement with L-methylfolate rather than folic acid to prevent folate-related complications and health issues. This is even more crucial during pregnancy. 

Folic acid is the un-methylated form and is not suitable as it must undergo a four-step enzymatic reduction process by dihydrofolate reductase (DHFR) to become biologically active.

Worse, an increase in unmetabolized folic acid (UMFA) can lead to many issues besides pregnancy complications. UMFA has been linked to immune dysfunction by dysregulation of natural killer cells and even an increased risk of some cancers. 

L-methylfolate, on the other hand, is the primary biologically active form of folate used by the body at the cellular level. It is immediately available for its many biological functions in the body (DNA reproduction, homocysteine conversion, neurotransmitter production, and more). 

L-methylfolate is used within the cell in the methylation of homocysteine to form methionine and tetrahydrofolate (THF). L-methylfolate is the only form that can be transported across membranes for uptake in the body’s tissues and also through the blood-brain barrier. It is directly available for gastrointestinal absorption. 

Supplementation with methylfolate has been shown to effectively improve folate biomarkers in young women in early pregnancy, which can prevent neural tube defects.

The US National Institutes of Health (NIH) and Institute of Medicine (IOM) have recommended that pregnant women take 600 µg of folic acid daily and continue this dosage throughout pregnancy (which was recommended to be reduced to 500 µg during lactation).

Pregnant women with an MTHFR mutation should avoid folic acid. Instead, they are advised to supplement with active methylfolate in a dosage of 600-800mcg.

Studies show that methylfolate bypasses the MTHFR block, which makes it an effective treatment for women with MTHFR. A dosage of  800 μg is found to be safe and does not have the potential adverse effects of the UMFA syndrome.

Other research shows that active methylfolate is more effective than folic acid in improving folate status and is recommended as an efficient and safe alternative.

With the enormous range of folate/folic acid/methylfolate supplements available now, finding the right supplement can be a battle. 

As explained above, the most biologically active folate supplements are those that include (6S)-5-methyltetrahydrofolate or (6S)-5-MTHF (which can also be denoted as: (6S)-5-methyl-tetrahydrofolic acid, calcium salt, L-methylfolate or (6S)-5-methyltetrahydrofolic acid, monosodium salt). A crystalline form is both pure and highly stable. 

Methyl-Life® products contain the most bioactive and pure form of folate available, Magnafolate® PRO. Studies have shown that Magnafolate® PRO is even more pure, stable and potent than competing brands Quatrefolic® and Extrafolate®. 

We specifically recommend our Methylated Multivitamin, Methylfolate 2.5 , or B-Methylated II supplements for use during pregnancy.

This is because Magnafolate® is built on a calcium crystalline molecule structure just like the pharmaceutical brand of L-Methylfolate. This calcium salt based L-5-Methyltetrahydrofolate with its effective ‘Type C’ crystal form offers superior particle size distribution, stability, dissolution, potency, bioavailability, and safety.